| 1. |
- Bravo, L, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 2. |
- Tabiri, S, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- Colvin, Michael T., et al.
(författare)
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Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils
- 2016
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 138:30, s. 9663-9674
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-β (Aβ) is a 39-42 residue protein produced by the cleavage of the amyloid precursor protein (APP), which subsequently aggregates to form cross-β amyloid fibrils that are a hallmark of Alzheimer's disease (AD). The most prominent forms of Aβ are Aβ1-40 and Aβ1-42, which differ by two amino acids (I and A) at the C-terminus. However, Aβ42 is more neurotoxic and essential to the etiology of AD. Here, we present an atomic resolution structure of a monomorphic form of AβM01-42 amyloid fibrils derived from over 500 13C-13C, 13C-15N distance and backbone angle structural constraints obtained from high field magic angle spinning NMR spectra. The structure (PDB ID: 5KK3) shows that the fibril core consists of a dimer of Aβ42 molecules, each containing four β-strands in a S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic cores that are capped at the end of the chain by a salt bridge. The outer surface of the monomers presents hydrophilic side chains to the solvent. The interface between the monomers of the dimer shows clear contacts between M35 of one molecule and L17 and Q15 of the second. Intermolecular 13C-15N constraints demonstrate that the amyloid fibrils are parallel in register. The RMSD of the backbone structure (Q15-A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ± 0.08 Å. The structure provides a point of departure for the design of drugs that bind to the fibril surface and therefore interfere with secondary nucleation and for other therapeutic approaches to mitigate Aβ42 aggregation.
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| 4. |
- Johnson, Candice, et al.
(författare)
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Skin sensitization in silico protocol
- 2020
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Ingår i: Regulatory toxicology and pharmacology. - : Elsevier BV. - 0273-2300 .- 1096-0295. ; 116
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Tidskriftsartikel (refereegranskat)abstract
- The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducing a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.
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| 5. |
- Khatri, C, et al.
(författare)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Tidskriftsartikel (refereegranskat)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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| 6. |
- McParland, Brian J., et al.
(författare)
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The clinical safety, biodistribution and internal radiation dosimetry of [F-18]fluciclovine in healthy adult volunteers
- 2013
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 40:8, s. 1256-1264
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Tidskriftsartikel (refereegranskat)abstract
- We report on the biodistribution and internal radiation dosimetry in humans of [F-18]fluciclovine, a synthetic L-leucine analogue being investigated as a potential diagnostic biomarker for neoplasia. Whole-body positron emission tomography (PET) scans of 6 healthy volunteers were acquired at up to 16 time points up to about 5 h after a bolus administration of [F-18]fluciclovine (153.8 +/- 2.2 MBq). Venous blood samples were taken up to about 4 h post-injection from which F-18 activity concentrations in whole blood and plasma were measured. Urine was collected as voided up to 4 h post-injection, from which the excreted F-18 activity was measured. Absolute values of the F-18 activity contained in up to 11 source regions (brain, salivary glands, lung, heart, pancreas, spleen, liver, red bone marrow, kidneys, uterus and urinary bladder contents) were determined directly from quantitative analysis of the images. For each source region, the F-18 activity decay-corrected and normalised to that injected, as a function of time, was fit by an analytical function which was subsequently integrated to yield the cumulated activity normalised to the injected activity. These normalised cumulated activities were then used as input to the Organ Level INternal Dose Assessment/EXponential Modelling (OLINDA/EXM) package to calculate the internal radiation dosimetry of each subject following the Medical Internal Radiation Dose (MIRD) schema. An effective dose was then estimated for each subject. [F-18]Fluciclovine was clinically well tolerated in this study. Very little F-18 was excreted with only a mean value of 3.3 % present in the urine at about 4 h post-injection; no activity within the intestinal contents was noted. The highest mean initial uptakes were measured in the liver (13.8 %), red bone marrow (11.1 %) and lung (7.1 %). The highest mean radiation absorbed doses per unit administered activity were received by the pancreas (102.2 mu Gy/MBq), the cardiac wall (51.7 mu Gy/MBq) and the uterine wall (44.6 mu Gy/MBq). The mean effective dose per unit administered activity was 22.1 mu Sv/MBq. The internal radiation dosimetry of [F-18]fluciclovine appears acceptable for PET imaging.
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| 7. |
- Raghavan, Maanasa, et al.
(författare)
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Genomic evidence for the Pleistocene and recent population history of Native Americans
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 349:6250
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Tidskriftsartikel (refereegranskat)abstract
- Howand when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we found that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (ka) and after no more than an 8000-year isolation period in Beringia. After their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 ka, one that is now dispersed across North and South America and the other restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative "Paleoamerican" relict populations, including the historical Mexican Pericues and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.
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| 8. |
- Singbrant, Sofie, et al.
(författare)
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The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease
- 2014
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 99:4, s. 647-655
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Tidskriftsartikel (refereegranskat)abstract
- The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.
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| 9. |
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